Previous studies revealed that PDZ binding kinase (PBK) is a serine/threonine kinase related to the dual specific mitogen-activated protein kinase kinase (MAPKK) family (Abe Y, et al., J Biol. Chem. 275: 21525-21531, 2000, Gaudet S, et al., Proc Natl Acad. Sci. 97: 5167-5172, 2000 and Matsumoto S, et al., Biochem Biophys Res Commun. 325: 997-1004, 2004). PBK was also indicated to be involved in mitosis as shown by its significant role in highly proliferating spermatocytes (Gaudet S, et al., Proc Natl Acad. Sci. 97: 5167-5172, 2000 and Fujibuchi T, et al., Dev Growth Differ. 47:637-44, 2005). In fact, abundant expression of PBK was observed in testis, while almost no PBK expression was detected in other normal organs (Park J H, et al., Cancer Res. 66: 9186-95, 2006). PBK regulates cell cycle progression. In accordance with this, its significant overexpression was detected in clinical breast cancer samples (Park J H, et al., Cancer Res. 66: 9186-95, 2006), Burkitt's lymphoma (Simons-Evelyn M, et al., Blood Cells Mol Dis. 27: 825-829, 2001) and a variety of hematologic malignancies (Nandi A, et al., Blood Cells Mol Dis. 32: 240-5, 2004).
Immunohistochemical analysis of testis revealed the expression of PBK protein around the outer region of seminiferous tubules where repeated mitosis of sperm germ cells followed by meiosis occurs (Fujibuchi T, et al., Dev Growth Differ. 47: 637-44, 2005). Especially, at prophase and metaphase, the subcellular localization of PBK was detected around the condensed chromosome in breast cancer cells (Park J H, et al., Cancer Res. 66: 9186-95, 2006). Moreover the knockdown of PBK expression with gene specific siRNAs caused dysfunction of cytokinesis and subsequently led to apoptosis of the cancer cells (Park J H, et al., Cancer Res. 66: 9186-95, 2006). These indicated the critical function of PBK at mitosis, in testicular and cancer cells.
Taken together, PBK-specific inhibitors can be used as a drug applicable for a broad spectrum of cancers. PBK is an excellent target for cancer therapy for the following reasons: i) almost no expression in normal organs (except for testis); ii) frequent overexpression in clinical cancer samples; iii) a serine/threonine kinase related to the essential function for cell mitosis.
The present inventors have found that a Tricyclic compound can selectively inhibit the activity of PBK.